PT-028 - ORAL PROGESTERONE-MEDIATED ATTENUATION OF IBUTILIDE-INDUCED QT INTERVAL LENGTHENING IN PREMENOPAUSAL AND POSTMENOPAUSAL WOMEN: POPULATION PHARMACOKINETIC/ PHARMACODYNAMIC MODEL

M. Yue¹, J. Tisdale², H. Jaynes³, B. Overholser², K. Sowinski³, R. Kovacs⁴, M. Heathman^5,6, S. Quinney⁷; ¹Purdue University, West Lafayette, IN, United State, ²College of Pharmacy, Purdue University, Indianapolis, IN, USA, ³Purdue University, ⁴School of Medicine, Indiana University, ⁵Metrum Research Group, Tariffville, CT, US, ⁶School of Medicine, Indiana University, Indianapolis, IN, US, ⁷School of Medicine, Indiana University, Indianapolis, IN, USA.

Background: Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation, which can be inherited or acquired. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. Our aim is to develop a PK/PD model to describe the effect of oral progesterone on ibutilide-induced QT interval lengthening and identify sources of variability.

Methods: Two randomized, double-blind, placebo-controlled, two-way crossover clinical trials are being conducted in healthy premenopausal women (NCT03834883) and healthy postmenopausal women (NCT04675788). Preliminary data from 10 premenopausal women and 7 postmenopausal women were included in this analysis. These subjects were randomized to receive 400mg progesterone or placebo daily for 7 days. On the 8th day of each phase, the QT-lengthening drug ibutilide (0.003 mg/kg) was administered via a 10-minute infusion. Time-matched serum ibutilide concentrations and electrocardiograms were collected serially at 14 time points over 8 hours. Serum progesterone and estradiol concentrations were obtained before ibutilide infusion during each phase. A population PK model of ibutilide and a PK/PD model of baseline corrected-QT interval were developed sequentially using NONMEM. Progesterone concentration will be incorporated as a covariate on ibutilide drug effect once unblinded.

Results: Ibutilide PK was best described by a two-compartment model with interindividual variability (IIV) on CL, V1, Q and V2, and a proportional residual error model. An Emax model with IIV on Emax and EC50 and a combined error model best described the PD component. To avoid unblinding, randomized groups A and B were incorporated instead of progesterone concentrations. Emax of the two groups were modeled separately (36.6 vs. 38.3ms). Emax in postmenopausal women was 13.1 ms lower than in premenopausal women.

Conclusion: Our model adequately characterized ibutilide PK and its QT interval lengthening effect. The higher Emax suggests more ibutilide induced QT lengthening in premenopausal women. The difference of Emax between group A and B reflects potential progesterone effect. Enrollment is still ongoing, and more data will be added to improve model robustness and allow future covariate analysis.